Selective estrogen receptor modulators (SERMs) generally refer to agents that exert or do not exert an estrogen effect depending on organs or tissues; for example, the agents have an antiestrogen effect on the uterus, mammary gland, etc., whereas they exert an estrogen effect on postmenopausal osteoporosis, serum cholesterol, cardiovascular system, etc. These agents are exemplified by tamoxifen, raloxifene, lasofoxifene, etc.; among these, lasofoxifene appears promising as a prophylactic or therapeutic agent of postmenopausal osteoporosis, and clinical tests thereof have currently been progressing in a large scale. The chemical structure of the lasofoxifene, (cis-6-phenyl-5-[4-(2-pyrrolidine-1-ylethoxyphenyl]-5,6,7,8-tetrahydronaphthalen-2-ol), is shown below.

The process for producing lasofoxifene is exemplified by the following two processes. In one of the processes, a starting compound of 2-bromo-5-methoxy-toluene is brominated to obtain 1-bromo-2-bromomethyl-4-methoxy-benzene, which is then used to alkylate ethylbenzoylacetate, then to undergo decarboxylation, thereby obtaining 3-(2-bromo-5-methoxy-phenyl)-1-phenyl-propane-1-one, which is then protected by ketalation and sequentially subjected to an introduction reaction of an alkoxybenzoyl group, diketonization, formation of a naphthalene ring by McMurry coupling reaction mitigated by titanium, and an introduction reaction of an N-ethyl-pyrrolidino side chain, thereby obtaining an intermediate of cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalene-1-yl)phenoxy]-ethyl}-pyrrolidine, followed by demethylation of a methoxy group on the tetrahydronaphthalene ring to obtain lasofoxifene (see Patent Document 1).
In the other process, a starting material of 1,4-dibromobenzene is reacted with 1-hydroxyethyl-pyrrolidine to obtain 1-[2-(4-bromophenoxy)ethyl]pyrrolidine, which is made into an organic cerium reagent then reacted with 6-methoxy-tetralone to obtain 1-{2-[4-(6-emthoxy-3,4-dihydronaphthalene-1-yl)phenoxy]ethyl}pyrrolidine. Afterwards, lasofoxifene is prepared through introduction of a bromo group into 2-position of a dihydronaphthalene ring, substitution of a bromo group with a phenyl group, hydrogenation reaction, and demethylation reaction of a methoxy group (see Patent Document 2).
However, the former process includes as many as 8 reaction steps from the starting compound to the lasofoxifene, and is thus far from an effective process.
In addition, the latter process includes a lower number of 6 reaction steps; however, in order to provide a drug substance of pharmaceutical grade, there is a disadvantage in that a coupling reaction should be carried out in the final synthesis stage with low yield using a heavy metal catalyst difficult to remove therefrom.
Furthermore, both of the processes are specialized for the production of lasofoxifene such that intermediate products in the production processes are inadequate for an intermediate for producing various lasofoxifene analogues.
Patent Document 1: Japanese Unexamined Patent Application, First Publication No. 2000-327670
Patent Document 2: Japanese Unexamined Patent Application, First Publication No. H10-503215